Dynamicity of Interactions Human SIRT-1 proteins

Recently Published article on SIRT- 1 interaction providing insights on large number of the Interactions exhibited by Sirt-1 proteins which is found to be associated with longetivity and Ageing process in C elegans , mice and budding yeast. The interaction dataset experimentally determined Interactions from various techniques. Visualization of network is carried out by Cytoscape and Spring embbeded Layout . In the article it has been stated about the second order network being scale free and small world with very high number of second order interactions. It would be interesting to have larger perspective of interactions at second order

Someof the Excerpts of GO studies of Sirt-1 proteins from the article is listed down

GO studies on the hub proteins inferred from our analysis suggest that they are involved in important biological processes related to gene regulation, Metabolism and proton co-transport
(Table 2S). In details, SLC25A3 is responsible for the inorganic phosphate transport into the mitochondrial matrix, either by proton co-transport or in exchange for hydroxyl ions [k, Entrez Gene description], while JUN interacts directly with specific target DNA sequences to regulate gene expression. The centrality analysis based on hub proteins showed SLC25A3, JUN, Sirt-1, RUVBL2 and MCF2L2 as important proteins of the network. Other Methods based on MCC, DMNC, MNC and EPC evidenced the same proteins as hub nodes along with EP300, YBX1, RPL38, AR and Sirt-2.
Genes associated with proteins and found significant in the interactome were analyzed by the BiNGO package in CytoScape. Sirt1 1st order interacting partners are involved into numerous biological processes. Sirt1 interactome is significantly involved Metabolism modulation related processes [Figure 4]. Sirt-2 in chromatin silencing at rDNA, RPS27L and RTN4 in regulating anti-apoptotic phenomena.
Certain processes, like chromatin remodeling and modification, involve many important proteins of the network like KAT2B, NCOR1, HDAC6, RRP8, HDAC2 and KAT2A. Moreover, TP53, Sirt-2, PPARGC1, CPS1 and JUN are responsible for the processes related to the response to starvation whereas the response to stress is regulated by NCOR1, MYOD1, KRT1, SIRT2, HDAC2, RPS3, RELA, FOXO1, HDAC6 and other proteins involved in ncRNA metabolic processes and in negative regulation of signaling pathways. In particular, the important processes like DNA binding activity transcription factor regulation and DNA repair are shown to have an involvement with proteins like Sirt-1, Sirt-2, TP53, PPARGC1A, JUN, EP300, HDAC2, HDAC6, KAT2A, Kat 2B, RELA, RB1, WRN, XRCC5 and XRCC6 (Figure 3S).
In particular, the sirtuin network shows that Sirt-2, HDAC6, HDAC2, Sirt-1, PPARGc1A, TRRAP are implicated in histone modification and histone deacetylation whereas SUV39H1 and DICER1 are involved in gene silencing phenomenon. The proteins in Sirt 1 interaction maps showed also different cellular localization and molecular function (Figure 4 and Table 4S). In details, Sirt family, ARNTL, WRN, EP300, SYNCRIP, JUN, RPS3 are proteins showing pleiotropicity in biological as well as in the cellular localization in the GO analysis maps. In fact, Sirt-1 interacts with cytoplasmic, nuclear, extracellular and mitochondrial proteins as found with a significant p value i.e. p; 0.0000005 that measures the statistical significance of the different essentialities of proteins implicated in the biological processes. RELA and JUN show interactions with mitochondrial proteins, Sirt-1 interacts with other cellular proteins in activating DNA repair and stress protection mechanisms.

Second order interaction of Sirt-1
The Sirt-1 second-degree interaction map is composed of 4691 nodes. These nodes correspond to different partners interacting by 221595 edges (Interactions). The second order network of Sirt-1 is scale free and small world network interacting with numerous proteins implicated in transcription and metabolism related processes. Sirt 1 has a high degree of interactions in second order interaction maps as it is having interactions with high number of proteins like PARP1 (inhibits Sirt activity) and NAMPT (regulates NAD+ levels) [Yang et al., 2006]. Analyzing centrality statistics and pattern of rearrangement of interacting nodes in Second order interactome of Sirt-1 will provide further insights on the variability in functionality, cellular localization and pleiotropicity nature of the SIRT interaction map.

“Happy SirTuinG”

Full Article can be accessed at :

Sharma A, Gautam VK, Costantini S, Paladino A and Colonna G (2012). Interactomic and pharmacological insights on human Sirt-1. Front. Pharmacol. 3:40. doi: 10.3389/fphar.2012.00040

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